Animal feed and process

ABSTRACT

A process for increased productivity in healthy animals comprising the administration of a compound of the formula ##STR1## or a pharmacologically acceptable acid addition salt thereof, wherein R 1  is lower alkyl of from 1 to 4 carbon atoms; R 2  is hydrogen, halogen, or lower alkyl of from 1 to 4 carbon atoms; R 3  and R 4  are the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, inclusive; haloalkyl, arylalkyl and ##STR2## wherein alkyl is from 1 to 4 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms, or aryl, and R 3  and R 4  taken together with --N═are a member selected from the group piperidine, morpholine, pyrazole, tribromopyrazole, N-methylpiperazine, pyrrole, pyrrolidine, pyrrolidone in association with the animal&#39;s feed, water, salt ration, or pharmacologically acceptable carrier. Compositions comprising a compound of the above formula for daily administration or long acting forms are disclosed.

DESCRIPTION BRIEF SUMMARY OF THE INVENTION

Broadly the present invention encompasses pharmacologically acceptabledosage form or a nutritionally adequate animal feed having dispersedtherein a formamidine compound of the Formula I in sufficientconcentration to provide increasing productivity and feed efficienciesin healthy meat-producing, milk-producing or egg-laying animals. Theinvention also includes the process of administering the compositions tohealthy meat-producing, milk-producing, egg-laying or wool-producinganimals.

BACKGROUND OF THE INVENTION

It has been found in recent years that meat-producing animals will gainmore weight and gain it faster when various classes of compounds such asvitamins, minerals, estrogens, antibiotics, and tranquilizers are addedto the diet. Although the presently available compounds are useful, newmaterials are still being sought that would produce weight gains morerapidly, to a greater extent, more efficiently with respect to feedintake at a lower cost and without undesirable side effects.

The formamidine compounds of the Formula 1 are known compounds and havepreviously been used as insecticidal agents.

DETAILED DESCRIPTION OF THE INVENTION

It is now possible by use of the present invention to obtain unexpectedresults in the feeding of meat-producing, milk-producing, or egg-layinganimals; that is to say, an increased rate of weight gain, an increasedamount of weight gain, an increase in milk production enhanced woolproduction, or increased rate of egg laying, as well as increased feedefficiency, can be obtained by the addition of minute quantities of acompound of the Formula I to the animals usual nutrient feed drinkingwater or salt block or by administering short or long-acting dosageforms.

The compounds of Formula I can exist in the non-protonated or in theprotonated or acid addition salt form, depending on the pH of theenvironment. They form stable protonates, i.e., mono- or diacid additionsalts, on treatment with pharmacologically acceptable acids, forexample, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,acetic, glycolic, succinic, tartaric, maleic, malic, pamoic,methanesulforic, cyclohexanesulfamic, and lactic acids.

The active ingredients of the Formula I are known and can be prepared bymethods disclosed in U.S. Pat. No. 3,998,969, issued Dec. 2, 1976.

Unless otherwise specified, all percentages are given on aweight-to-weight basis. The pound (lb) weights given are avoirdupoisunits.

Administration of the compositions of the present invention can commencefor birds shortly after hatching and in the case of mammals, during thecreep-feeding period of suckling animals when they are starting on solidfood and, of course, after weaning. Feeding of the compositions iscontinued throughout the growing period, lactation period, or egg-layingperiod. In addition to feeding the active ingredient in combination withthe feed, the active compounds can alternatively be administered incombination with the animals drinking water or in combination with apharmaceutical carrier by injection or implantation.

The total concentration of the compound of the Formula I in the feedcomposition is determined with regard to the species of animal, sex,age, weight, and average amount of feed consumed daily. Preferably thecompound of the Formula I is employed in the finished feed that willsupply the animal with a daily intake of from about 0.02 mg to about 200mg per head, per day.

The following table illustrates the range of compound of Formula I inmilligrams daily dose, per head, per day for representative animals.

    ______________________________________                                                    Range            Preferred                                        Animal      Daily Dose/Head, mg                                                                            Daily Dose, mg                                   ______________________________________                                        Swine (birth to                                                                           0.5-20.0         10.0                                             8 weeks)                                                                      Swine (40 to 200                                                                          1.0-140.0        10.0                                             lbs)                                                                          Chickens (growing                                                                         0.02-2.0         0.05                                             0-8 weeks)                                                                    Hens (laying)                                                                             0.1-2.0          1.0                                              Turkeys (growing                                                                          0.1-5.0          2.0                                              0-24 weeks)                                                                   Beef Cattle 0.5-50.0         10                                               (fattening)                                                                   Calves      1.0-40.0         10                                               (0-12 weeks)                                                                  Dairy Cattle                                                                              5.0-200.0        10                                               (lactation)                                                                   Lambs       1.0-20.0         10                                               (fattening)                                                                   ______________________________________                                    

The foregoing dosages can generally be accomplished by providing fromabout 50 mg to about 20,000 mg of a compound of the Formula I per ton offinished feed.

Advantageously, a compound of the Formula I is supplied in the form of aliquid or solid premix wherein the concentration is 100-2,000 timesgreater than the desired final concentration in the feed. For example,the compound of Formula I can be dissolved or suspended in a fluidvehicle such as corn oil, cottonseed oil, molasses, distillers solublesand the like to prepare a fluid premix. Alternatively, a solid premixcan be prepared by mixing a compound of the Formula I with an ediblesolid diluent such as sucrose, lactose, starch, corn meal, flour,calcium carbonate, soybean meal and the like.

EXAMPLE 1

A diet for fattening lambs is prepared from the following types andamounts of ingredients:

    ______________________________________                                        Ground ear corn    82.35%                                                     Alfalfa meal       10.0%                                                      Soybean oil meal 44%                                                                             7.0%                                                       Ground limestone   0.3%                                                       Salt               0.3%                                                       Trace mineral mixture.sup.1                                                                      0.05%                                                      ______________________________________                                         .sup.1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe,      5.0; Cu, 0.4; I, 0.24; Zn, 0.7.                                          

The above feed to be mixed, pelleted and offered to fattening lambsfree-choice in conjunction with hay.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 7 gm ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine withsufficient corn meal to make one pound.

The feeding composition so prepared supplies 7.0 mg ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine per pound or15.4 parts per million.

The foregoing composition is usefully fed to lambs for increased rate ofweight gain and improved utilization of feed.

EXAMPLE 2

A chicken feed for broilers is prepared from the following types andamounts of ingredients:

    ______________________________________                                        Yellow corn meal   67.35%                                                     Soybean oil meal   24.00%                                                     Menhaden fish meal 6.00%                                                      Steamed bone meal  1.00%                                                      Ground limestone   1.00%                                                      Iodized salt       .34%                                                       25% Choline chloride                                                                             .13%                                                       Vitamin B.sub.12 supplement                                                   (6 mg/lb)          .10%                                                       Manganese sulfate  .02%                                                       Supplemental vitamin mix.sup.1                                                .06%                                                                          ______________________________________                                         .sup.1 Consisting of 16.0 gm Vitamin A supplement (10 units/mg; 3.6 gm        Vitamin D.sub.3 supplement (15,000 units/gm); 7.1 gm riboflavin supplemen     (1 gm riboflavin per ounce); 500 mg niacin.                              

To 999 parts of the preceding feed is added 1 parts of a premixcomposition prepared by mixing 0.38 gm ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine withsufficient soybean mill feed to make 1 pound.

The feeding composition so prepared supplies 0.38 mg ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine per pound, orabout 0.83 parts per million.

The foregoing composition is usefully fed to chickens for increased rateof weight gain and improved utilization of feed. Similarly thecomposition can be fed to turkeys, ducks and geese.

EXAMPLE 3

A fattening feed for 800 pound yearling cattle is prepared from thefollowing types and amounts of ingredients:

    ______________________________________                                        Ground ear corn   89.75%                                                      Soybean oil meal, 44%                                                                           9.0%                                                        Ground limestone  0.7%                                                        Salt              0.5%                                                        Trace mineral mixture.sup.1                                                                     0.05%                                                       ______________________________________                                         .sup.1 Contains the following percent of minerals: Mn, 12, Co, 0.08; Fe,      5.0; Cu, 0.4; I, 0.24; Zn, 0.7.                                          

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 0.5 gm ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine withsufficient wheat flour to make 1 pound.

The feeding composition so prepared supplies 0.5 mg ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine per pound, orabout 1.10 parts per million.

Cattle are to receive the foregoing feed ad libitum together with 5 lbs.of hay, per head, per day and when so fed have an increased rate ofweight gain and improved utilization of feed.

EXAMPLE 4

A swine diet for growing hogs of 40 to 100 pounds body weight isprepared from the following types and amounts of ingredients:

    ______________________________________                                        Corn, ground         78.15%                                                   Soybean oil meal, 44%                                                                              17.0%                                                    Meat and bone scraps, 50%                                                                          3.0%                                                     Oyster shell flour   0.4%                                                     Bone meal            0.5%                                                     Salt                 0.5%                                                     Trace mineral mixture                                                                              0.05%                                                    Zinc oxide           0.01%                                                    Vitamin A and D Supplement.sup.2                                                                   0.25%                                                    Vitamin Supplement.sup.3                                                                           0.05%                                                    Vitamin B.sub.12 supplement.sup.4                                                                  0.09%                                                    ______________________________________                                         .sup.1 Contains the following % of minerals: Mn, 12; Co, 0.08; Fe, 5.0;       Cu, 0.4; I, 0.24; Zn, 0.7.                                                    .sup.2 Contains 300 USP units D.sub.2 /Gm and 1500 IU of A/Gm                 .sup.3 Contains per lb: Riboflavin, 2000 mg; calcium pantothenate, 4000       mg; niacin, 9000 mg; and choline chloride 10,000 mg.                          .sup.4 Contains 6 mg Vitamin B.sub.12 per lb.                            

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 2 g ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine withsufficient ground limestone to make one pound.

The feeding composition so prepared supplies 2 mg ofN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine per pound orabout 4.4 parts per million.

The foregoing composition is usefully fed to hogs for increased rate ofweight gain and improved utilization of feed.

EXAMPLE 5

A regimen of N-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidinein water is prepared simply by adding the compound to the drinking wateras specified below. The animals are allowed to ingest the water on an adlibitum basis

    ______________________________________                                                              mg/l                                                    ______________________________________                                        Swine          Birth to 8 weeks                                                                           2.5                                               Swine          40-200 lb    7.0                                               Chickens       0-8 weeks    0.3                                               Hens                        5.0                                               Turkeys        0-24 weeks   3.2                                               Beef cattle                 0.2                                               Calves         0-12 weeks   1.0                                               Dairy cattle                0.9                                               Lambs                       5.0                                               ______________________________________                                    

In addition to the daily administration of a compound of the Formula Iin association with the animal feed or drinking water, dailyadministration can be accomplished by incorporation of the activecompound in a salt block in an amount calculated to provide the activecompound based upon the daily salt intake of the animal.

In animals that are on open range of for whom daily administration isinconvenient a long active carrier can be prepared for the activecompound. Long acting forms can be implants which are placed under theanimals skin, injectable fluids or in the case of ruminants, an oralbolus.

Implants are prepared for 30 or 90 day administration incorporating 30to 90 times the daily dose in an inert carrier material. The carriermaterial can be non-degradable by the animals body, e.g. siliconerubber, polyethylene or hydrophilic polymers such as hydron, ordegradable polymers such as polyactic acid, polyacetic acid/polyglycolicacid copolymer, poly(ortho-ester), poly(E-caprolactone) or polyglutamicacid. Implants are conveniently implanted in the neck of the chicken,the dewlap of the calf, ear of the pig, or flank of goats and lambs,

Long acting (90 day) injectable can be prepared incorporated 90 timesthe daily dose of a compound of the Formula I in combination with asterile injectable fluid carrier such as water, polyethylene glycol 400,propylene glycol or water.

Long acting orally administered forms, e.g., a bolus can be prepared forruminant animals. The bolus can be prepared by the same materials as theimplant but is made in a much larger size and advantageously has addedexcipients to increase the specific gravity of the devise. The boluswhen administered remains in the reticulum or rumen of the animal andreleases the drug over the desired period of time. Excipients toincrease specific gravity can be for example, iron pellets, calciumsulfate dihydrate portland cement or plaster of paris.

EXAMPLE 6 Salt Block

Salts blocks are prepared for cattle containing for 0.001 to 0.04percent w/w with 0.004 percent w/w being preferred. The cattle areallowed free access to the salt block for self administration adlibitum.

Salt blocks for sheep are prepared in a concentration of from 0.0024 to0.048 percent w/w with 0.024 being preferred.

EXAMPLE 7 Long Acting Injectable Fluid

A long acting injectable fluid is prepared by the following types andamount of ingredients:

    ______________________________________                                        N--methyl-N--[(dimethylamino)thio]-                                           N'--2,4-xylyl formamidine                                                                              1.8    gram                                          Benzyl alcohol           0.1    gram                                          Carboxymethylcellulose   0.1    gram                                          NaCl                     0.09   gram                                          Tween 80                 0.1    gram                                          Propylene glycol q.s.    10.    ml                                            ______________________________________                                    

The ingredients are mixed under aseptic conditions.

The composition when injected, 5 ml, into calves, beef or dairy cattleor lambs provides 10 mg of drug 1 day for 90 days.

EXAMPLE 8 Implant

A silicone rubber implant is prepared for the following types andamounts of ingredients.

    ______________________________________                                        N--methyl-N--[(dimethylamino)thio]-                                           N'--2,4-xylyl formamidine                                                                              0.72   gram                                          Stannous octoate         0.26   gram                                          Dimethylpolysiloxane (Dow Corning                                             Silastic 382)            99.    gram                                          ______________________________________                                    

The ingredients are mixed well and placed in a cylindrical mold andcured.

The silastic device is implanted on the dewlap of a calf or flank of asheep or goat for 90 days of release.

For pigs the active compound is increased to 3.6 gram and the deviceplaced in the tissue under the ear.

EXAMPLE 9 Bolus for Ruminants

(A) A thirty day bolus is prepared for the following types and amount ofingredients.

    ______________________________________                                        N--methyl-N--[(dimethylamino)thio]-                                           2,4-xylyl formamidine    .3     gram                                          Mg stearate              .5     gram                                          CaSO.sub.4 dihydrate q.s.                                                                              100.0  gram                                          ______________________________________                                    

The bolus is prepared by mixing the ingredients together andcompression. The bolus provides 30 days treatment for goats, sheep orcattle.

    ______________________________________                                        (B) 90 Day bolus                                                              ______________________________________                                        N--methyl-N--[(dimethylamino)thio]-N'--                                       2,4-xylyl formamidine    .9     gram                                          Mg stearate              .5     gram                                          CaSO.sub.4 dihydrate q.s.                                                                              100.0  gram                                          ______________________________________                                    

The bolus is prepared by mixing the ingredients and compression. Thebolus provides 90 days treatment for goats, sheep or cattle.

EXAMPLE 10

Following the procedure of the preceding Examples 1 through 9,inclusive, compositions are similarly prepared substituting an equalamount each of

N-methyl-N-[(diphenylamino)thio]-N'-(2-methyl-4-chlorophenyl)formamidine,

N-methyl-N-[(methylcyclohexylamino)thio]-N'-(2-methyl-4-chlorophenyl)formamidine,

N-methyl-N-[(dibenzylamino)thio]-N'-(2-methyl-4-chlorophenyl)formamidine,

N-methyl-N-[(diisopropylamino)thio]-N'-(2-methyl-4-chlorophenyl)formamidine,

N-methyl-N-[(di-n-butylamino)thio]-N'-(2-methyl-4-chlorophenyl)formamidine,

N-methyl-N-[(diisopropylamino)thio]-N'-(2-methyl-4-bromophenyl)formamidine,

N-methyl-N-[(N-ethylanilino)thio]-N'-2,4-xylyl formamidine,

N-methyl-N-[(N-methylanilino)thio]-N'-(2-methyl-4-chlorophenyl)formamidine, and

N-methyl-N-[(N-ethylanilino)thio]-N'-(2-methyl-4-chlorophenyl)formamidine for the N-methyl-N-[(dimethylamino)thio]-N'-2,4-xylylformamidine.

The active compound of the invention are a compound of the formula##STR3## or a pharmacologically acceptable acid addition salt thereof,wherein R₁ is lower alkyl of from 1 to 4 carbon atoms; R₂ is hydrogen,halogen, or lower alkyl of from 1 to 4 carbon atoms; R₃ and R₄ are thesame or different and are hydrogen, alkyl of 1 to 8 carbon atoms,inclusive; haloalkyl, arylalkyl and ##STR4## wherein alkyl is from 1 to4 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms, or aryl, and R₃and R₄ taken together with --N═ are a member selected from the grouppiperidine, morpholine, pyrazole, tribromopyrazole, N-methylpiperazine,pyrrole, pyrrolidine, pyrrolidone.

I claim:
 1. A process for obtaining increased meat, milk, egg, or woolproduction in healthy animals comprising the daily feeding of aneffective amount of a compound of the formula ##STR5## or apharmacologically acceptable acid addition salt thereof, wherein R₁ islower alkyl of from 1 to 4 carbon atoms; R₂ is hydrogen, halogen, orlower alkyl of from 1 to 4 carbon atoms; R₃ and R₄ are the same ordifferent and are hydrogen, alkyl of 1 to 8 carbon atoms, inclusive;haloalkyl, arylalkyl and ##STR6## wherein alkyl is from 1 to 4 carbonatoms, cycloalkyl of from 3 to 6 carbon atoms, or aryl, and R₃ and R₄taken together with --N═ are a member selected from the grouppiperidine, morpholine, pyrazole, tribromopyrazole, N-methylpiperazine,pyrrole, pyrrolidine, pyrrolidone in association with the animal's feed,water, salt ration, or pharmacologically acceptable carrier.
 2. Theprocess of claim 1 wherein the compound isN-methyl-N-[(dimethylamino)thio]-N'-2,4-xylyl formamidine.
 3. A processfor obtaining increased meat, milk, egg, or wool production in healthyanimals comprising the administration of a long acting compositioncontaining an effective amount of a compound of the formula ##STR7## ora pharmacologically acceptable acid addition salt thereof, wherein R₁ islower alkyl of from 1 to 4 carbon atoms; R₂ is hydrogen, halogen, orlower alkyl of from 1 to 4 carbon atoms; R₃ and R₄ are the same ordifferent and are hydrogen, alkyl of 1 to 8 carbon atoms, inclusive;haloalkyl, arylalkyl and ##STR8## wherein alkyl is from 1 to 4 carbonatoms, cycloalkyl of from 3 to 6 carbon atoms, or aryl, and R₃ and R₄taken together with --N═ are a member selected from the grouppiperidine, morpholine, pyrazole, tribromopyrazole, N-methylpiperazine,pyrrole, pyrrolidine, pyrrolidone, said composition being in the form ofan implant, bolus, or sterile injectable.
 4. The process of claim 3wherein the compound is N-methyl-N-[(dimethylamino)thio]-N'-2,4-xylylformamidine.